Από του στόματος χορηγούμενα αντιπηκτικά. Μηχανισμοί δράσης-κλινική αποτελεσματικότητα

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1 ΠΑΝΕΠΙΣΤΗΜΙΟ ΙΩΑΝΝΙΝΩΝ ΔΠΜΣ Ιατρική Χημεία Από του στόματος χορηγούμενα αντιπηκτικά. Μηχανισμοί δράσης-κλινική αποτελεσματικότητα Αλέξανδρος Δ. Τσελέπης, MD, PhD Καθηγητής Βιοχημείας Κλινικής Χημείας

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3 Oral Anticoagulant Target Sites Factor IX Factor VII Factor X FVIIa Anti-FXa Apixaban Rivaroxaban Edoxaban FIXa Factor Xa Antithrombin VKA Warfarin Factor II (Prothrombin) Factor IIa (Thrombin) Anti-FIIa Dabigatran Fibrinogen Fibrin

4 Coumarin Derivatιves e.g. Warfarin Mechanism of action Vitamin K epoxide Vitamin K reduced Inactive factors II, VII, IX, and X Proteins S and C Active factors II, VII, IX, and X Proteins S and C Prevents the reduction of vitamin K, which is essential for activation of certain factors Has no effect on previously formed thrombus

5 Ο κύκλος της Βιταμίνης K VKOR subunit 1 (VKORC1) C1173T polymorphism Marín F, et al. J Am Coll Cardiol 2009;54:

6 Μηχανισμός δράσης ανταγωνιστών της Βιταμίνης Κ Βιταμίνη K Ανταγωνισμός της Βιταμίνης Κ VII IX X II Σύνθεση μη λειτουργικών παραγόντων πήξης Warfarin

7 Vit K Antagonists Slow onset and offset of action Protein Half Life (Hours) Prothrombin (II) Factor VII 6-8 Factor IX Factor X Protein C 8-10 Protein S 40-60

8 Mechanism of Action of Vit K Antagonists

9 New Oral Anticoagulants Bauer KA J Thromb Haemost 2011; 9 (Supl):12-19

10 New Oral Anticoagulants

11 Comparison of the active center in the crystal structures of thrombin and factor Xa Thrombin Xa Flat Large Deep Straub A, et al. Angew. Chem. Int. Ed. 2011, 50,

12 Binding of Dabigatran and Rivaroxaban to thrombin and Fa Dabigatran-Thrombin Rivaroxaban-Xa Straub A, et al. Angew. Chem. Int. Ed. 2011, 50,

13 Binding mode of apixaban Wong PC, et al. J Thromb Thrombolysis (2011) 31:

14 Δράση των άμεσων αναστολέων της Θρομβίνης FXa στο σύμπλεγμα της Προθρομβινάσης Άμεσοι Αναστολείς της Θρομβινης FΙΙa στο Ινώδες FΙΙa Οι άμεσοι αναστολείς της θρομβίνης αναστέλλουν τόσο τη ελεύθερη όσο και τη δεσμευμένη στο ινώδες θρομβίνη

15 Δράσεις των άμεσων αναστολέων του Xa FXa στο σύμπλεγμα της Προθρομβινάσης Άμεσοι Αναστολείς του Fxa FXa στο Ινώδες FXa Οι άμεσοι αναστολείς του Xa αναστέλλουν τόσο τον ελεύθερο όσο και τον δεσμευμένο Xa στο σύμπλεγμα της προθρομβινάσης και στο ινώδες

16 Comparison of the characteristics of new oral anticoagulants Protein binding >90% >87% 55% 35% (dialysable) Weitz JI, et al. Thromb Res. 127 Suppl. 2 (2011) S5 S12

17 Dabigatran Etexilate Dabigatran Amidine group High polarity not oraly available Dabigatran etexilate Oraly available + tartaric acid Dabigatran etexilate: προφάρμακο Εστεράσες Dabigatran: ενεργός μεταβολίτης

18 Dabigatran etexilate

19 Comparison of the characteristics of new oral anticoagulants (Active 36%) Active 36% Inactive 30% Protein binding >90% >87% 55% 35% (dialysable) Hepatic metabolism CYP3A4 CYP3A4 CYP3A4 Conjugation Weitz JI, et al. Thromb Res. 127 Suppl. 2 (2011) S5 S12

20 Renal Profiles of Anticoagulants Dabigatran Rivaroxaban. Apixaban excretion is also partly dependent on renal function Harder S. J Clin Pharmacol, 2012,

21 Clinical Pharmacology of the new oral anticoagulants Potpara TS, et al. Adv Ther (2012) 29(6):

22 Mean plasma concentration-time profiles of Dabigatran in healthy volunteers and patients with moderaten hepatic impairment, after a single 150-mg dose of dabigatran etexilate Stangier J, et al. J Clin Pharmacol, 2008;48:

23 New Oral Anticoagulants In AF RE-LY ARISTOLE ROCKET-AF

24 RE-LY Safety Outcomes Connolly SJ et al. N Engl J Med 2009;361:

25 ROCKET-AF Rates of Bleeding Events Connolly SJ et al. Presented at ESC 2010 Patel MR, et al. NEJM. 2011

26 ARISTOTLE: Bleeding Outcomes Outcome Primary safety outcome: ISTH major bleeding* Apixaban (N=9088) Event Rate (%/yr) Warfarin (N=9052) Event Rate (%/yr) HR (95% CI) P Value (0.60, 0.80) <0.001 Intracranial (0.30, 0.58) <0.001 Gastrointestinal (0.70, 1.15) 0.37 Major or clinically relevant non-major bleeding (0.61, 0.75) <0.001 GUSTO severe bleeding (0.35, 0.60) <0.001 TIMI major bleeding (0.46, 0.70) <0.001 Any bleeding (0.68, 0.75) <0.001 Granger CB, et al. N Engl J Med 2011; 365:

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28 Prothrombin Time (PT) INR

29 Thrombin Time (TT)

30 Vit K Antagonists: Require monitoring (PT, INR) Courtesy of Patrik Michel, adapted from Hylek et al. NEJM 1996; 335:540-6

31 Nο Laboratory Monitoring in Daily Practice Predictable pharmacokinetics and pharmacodynamics Rapid onset of action Wide therapeutic window Fixed dose Clinical trials without monitoring

32 Laboratory Monitoring is Sometimes necessary Bleeding or thrombotic event High risk for bleeding Elective or urgent surgery Suspected overdose Renal or hepatic dysfunction Bridging from one anticoagulant to another Compliance monitoring Pts with low body weight or obese pts Co-medications (potential drug interactions)

33 Rivaroxaban Monitoring

34 Prothrombin Time (s) Correlation between PT and Rivaroxaban plasma concentration 40 Prothrombin time Model r = Plasma Concentration of Rivaroxaban (µg/l) Perzborn et al. JTH; 2005; Hillarp et al JTH; 2011

35 Validation of the efficacy of the rivaroxaban-standardized prothrombin time (PT) ratio (Riva-PT-ratio) PT ratio = (PT patient / PT normal ) INR = (PT patient / PT normal ) ISI Riva PT ratio = (PT patient / PT normal ) RivaSI Tripodi A. JTH. 2012;11:

36 Anti-Xa activity of rivaroxaban : Chromogenic method Samama MM, et al. Thromb Haemost. 2010

37 Apixaban monitoring Limited information available Minimal impact on PT and APTT Increases Dilute Prothrombin time (diluted thromboplastin reagents) in a concentration dependent manner Prolongs Hep test Chromogenic anti-factor Xa assays - promising results/variability

38 Dabigatran Monitoring

39 Effect of dabigatran on clotting tests *** * *** * Van Ryn et al Thromb Haemost 2010

40 The HCT test for Dabigatran Dabigatran

41 Correlation of HCT test with plasma concentration of Dabigatran Van Ryn et al Thromb Haemost 2010

42 Influence of NOACs on clotting tests PT aptt TT or Ecarin Clotting Time Dabigatran Rivaroxaban Apixaban Anti-Xa Anti-IIa (HCT)